MicroRNA-424在腫瘤發(fā)生中的作用和機(jī)制研究進(jìn)展

劉萍，趙海蘋，羅玉敏，*

(1.首都醫(yī)科大學(xué)宣武醫(yī)院神經(jīng)內(nèi)科，北京 100053； 2. 首都醫(yī)科大學(xué)宣武醫(yī)院腦血管病研究室，北京 100053)

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MicroRNA-424在腫瘤發(fā)生中的作用和機(jī)制研究進(jìn)展

劉萍1，趙海蘋2，羅玉敏1，2*

(1.首都醫(yī)科大學(xué)宣武醫(yī)院神經(jīng)內(nèi)科，北京 100053； 2. 首都醫(yī)科大學(xué)宣武醫(yī)院腦血管病研究室，北京 100053)

MiR-424是miR-16家族成員。近年研究表明miR-424與腫瘤的發(fā)生、發(fā)展及治療預(yù)后密切相關(guān)。本文對miR-424在乳腺癌、宮頸癌、肺癌、肝癌及結(jié)直腸癌等多種腫瘤及白血病中的表達(dá)變化、作用及機(jī)制進(jìn)行綜述。研究發(fā)現(xiàn)miR-424的表達(dá)受多種因素的影響，miR-424可作為腫瘤診斷、分期、預(yù)后的生物標(biāo)記物，可用于明確腫瘤范圍，也可作為腫瘤的治療靶物。

miR-424；腫瘤；白血病

MiR-424是miR-16家族成員。MiR-16家族的種子序列為5’端種子區(qū)的第二個核苷酸開始出現(xiàn)AGCAGC (AGCx2)序列，該家族在細(xì)胞周期、增殖、凋亡及存活等過程中有重要作用。MiR-16家族主要包括miR-15a/b、miR-16、miR-195、miR-424和miR-497。其中miR-424的基因位于染色體Xq26.3上，在鼠類其同源物為miR-322。MiR-424可與miR-503聚集，從相同的初級轉(zhuǎn)錄物中轉(zhuǎn)錄[1]。成熟的miR-424也可與miR-450b形成簇[2]。研究表明，miR-424與腫瘤的發(fā)生發(fā)展及治療預(yù)后密切相關(guān)，本文對miR-424在腫瘤中的表達(dá)變化、作用及機(jī)制進(jìn)行綜述。

研究發(fā)現(xiàn)miR-424在鱗狀細(xì)胞癌、非小細(xì)胞肺癌、腎癌、胰腺癌中表達(dá)均上調(diào)；在宮頸癌、子宮內(nèi)膜癌、卵巢癌、前列腺癌、結(jié)腸癌、肺癌中表達(dá)均下調(diào)[3-9]。Ratert等[10]發(fā)現(xiàn)在膀胱上皮癌中miR-424表達(dá)與正常組織相比差異無顯著性。表明miR-424在不同種類癌癥中的表達(dá)變化不同，可能是因為miR-424在不同組織和器官中的作用不同。

1 乳腺癌

臨床研究顯示，miR-424可作為乳腺癌診斷、預(yù)后的標(biāo)記物。Dvinge等[11]發(fā)現(xiàn)約8%的激素受體陽性的乳腺癌中miR-424/503基因所在的染色體位置出現(xiàn)嚴(yán)重缺陷。Zhang等[12]分析微量人血清標(biāo)本發(fā)現(xiàn)miR-424結(jié)合miR-199a、miR-29c可用于篩查出早期乳腺癌患者，敏感性為77%，特異性為92%，與乳腺鉬靶照相技術(shù)相仿。Lerebours等[13]發(fā)現(xiàn)浸潤性乳腺癌中miR-424表達(dá)升高，可見miR-424高表達(dá)與乳腺癌浸潤性有關(guān)，預(yù)示不良預(yù)后。

MiR-424可促進(jìn)乳腺癌細(xì)胞的增殖、轉(zhuǎn)移和浸潤。Cicatiello等[14]發(fā)現(xiàn)雌激素刺激乳腺癌細(xì)胞系 MCF-7時miR-424顯著高表達(dá)，參與了雌二醇應(yīng)答基因網(wǎng)絡(luò)。Anne等[2]報道雌激素可上調(diào)MCF-7細(xì)胞中miR-424表達(dá)以促進(jìn)增殖，該作用可被維甲酸抑制。Li等[15]也指出轉(zhuǎn)移性高的乳腺癌中miR-424/503簇表達(dá)顯著升高，過表達(dá)miR-424/miR-503可下調(diào)轉(zhuǎn)化生長因子-β信號通路的抑制因子包括Smad7和Smad泛素化調(diào)節(jié)因子-2(Smurf2)的蛋白水平表達(dá)，并增強(qiáng)乳腺癌的轉(zhuǎn)移能力；而下調(diào)乳腺癌細(xì)胞中miR-424/miR-503的表達(dá)時可抑制細(xì)胞轉(zhuǎn)移，延長患者生存期。Pincini指出正常乳腺細(xì)胞MCF-10A細(xì)胞過表達(dá)信號分子(p130 Crk-associated substance, p130Cas)并活化原癌基因erbB-2后表現(xiàn)出浸潤特性，同時MCF-10A細(xì)胞miR-424表達(dá)顯著增高[16]。Drasin等[17]指出在轉(zhuǎn)錄因子TWIST1 或鋅指轉(zhuǎn)錄因子SNAI1誘導(dǎo)的上皮間質(zhì)轉(zhuǎn)化中miR-424表達(dá)上調(diào)，可增加細(xì)胞活動性、減少粘連并誘導(dǎo)生長阻滯；乳腺癌原位腫瘤與正常乳腺組織比較miR-424表達(dá)增加，且miR-424表達(dá)與TWIST1/2和EMT相關(guān)基因呈正相關(guān)；轉(zhuǎn)移腫瘤的miR-424表達(dá)比原位腫瘤低，可見miR-424在EMT-MET軸中有雙向性，提示miR-424在腫瘤進(jìn)展中可能具有雙向作用：早期促進(jìn)、晚期抑制。

2 宮頸癌、子宮內(nèi)膜癌

臨床研究顯示，miR-424對宮頸癌的診斷和預(yù)后具有提示作用。與正常宮頸上皮組織比較，重度宮頸上皮內(nèi)瘤變(cervical intraepithelial neoplasia，CIN)病灶組織的miR-424表達(dá)上調(diào)，結(jié)合其余11個miRs的變化可用于區(qū)分宮頸上皮內(nèi)瘤變與正常上皮[18]。然而，Tian發(fā)現(xiàn)未明確意義的組織學(xué)異常上皮細(xì)胞中miR-424表達(dá)較正常宮頸細(xì)胞下降，并且，與HPV+的輕度CIN比較，HPV+的重度CIN組織中miR-424表達(dá)下降；與巴氏檢測比較，miR-424結(jié)合miR-375與miR-218用于檢測HPV+的2級以上宮頸上皮內(nèi)瘤變具有更高的敏感性，且特異性相當(dāng)[19]。與正常增殖宮頸內(nèi)皮比較，高分化腺癌—宮頸微偏腺癌的miR-424-5p表達(dá)下降[20]。高危型人乳頭瘤病毒陽性(HR-HPVs+)的宮頸癌組織與HR-HPV-的正常宮頸組織比較miR-424表達(dá)顯著下降，提示miR-424可能作為宮頸癌的診斷和預(yù)后生物標(biāo)記物[21, 22]。Xu等[23]也發(fā)現(xiàn)miR-424在宮頸癌組織中表達(dá)顯著下降，并且miR-424的低表達(dá)與腫瘤低分化、高臨床分期、淋巴結(jié)轉(zhuǎn)移等提示不良預(yù)后的病理參數(shù)呈正相關(guān)。但Cheung等[18]比較宮頸癌病灶組織與正常宮頸上皮的miRs表達(dá)，未發(fā)現(xiàn)miR-424在二者間出現(xiàn)顯著表達(dá)差異。推測與Cheung等僅用基因芯片檢測且入選例數(shù)少有關(guān)。

miR-424可抑制宮頸癌、子宮內(nèi)膜癌細(xì)胞的生長、轉(zhuǎn)移和浸潤。在宮頸癌細(xì)胞系SiHa及CaSki中miR-424過表達(dá)可促進(jìn)凋亡、阻滯G1/S轉(zhuǎn)化，抑制細(xì)胞生長、轉(zhuǎn)移和浸潤；miR-424直接靶向蛋白檢查點(diǎn)激酶1(Chk1)的mRNA，下調(diào)Chk1和p-Chk1蛋白水平，下調(diào)基質(zhì)金屬蛋白酶MMP-9[21, 23]，提示miR-424可能成為宮頸癌的抗癌治療靶點(diǎn)。Li等[7]發(fā)現(xiàn)子宮內(nèi)膜癌組織及人子宮內(nèi)膜癌細(xì)胞系Ishikawa和HEC-1B中miR-424表達(dá)均降低，而miR-424靶向抑制轉(zhuǎn)錄調(diào)節(jié)因子E2F7，可抑制子宮內(nèi)膜癌細(xì)胞生長。

3 肺癌

研究顯示，肺癌患者組織中miR-424的高表達(dá)提示其預(yù)后較差。Chen等[24]發(fā)現(xiàn)在肺癌細(xì)胞系及患者病灶組織中miR-424表達(dá)顯著增加，并可能靶向THBS1 及 RGS5。Donnem等[25]發(fā)現(xiàn)非小細(xì)胞肺癌患者中，生存時間短的患者miR-424的表達(dá)明顯高于生存時間長的患者，這可能與miR-424促血管生成有關(guān)。與此相似，接受化療的晚期非鱗狀非小細(xì)胞肺癌患者外周血中miR-424結(jié)合miR-29a、miR-542-5p、miR-502-3p、miR-376a和miR-500a可預(yù)測患者總生存期，miR-424高表達(dá)時總生存期縮短[26]。此外，Berghmans等[27]發(fā)現(xiàn)用順鉑和長春瑞濱治療的非小細(xì)胞肺癌患者中支氣管鏡肺活檢組織miR-424表達(dá)結(jié)合miR-200c、miR-29c和 miR-124組成參數(shù)公式，可用于預(yù)測患者預(yù)后好壞及腫瘤進(jìn)展快慢。

4 肝癌

臨床研究顯示， miR-424在肝癌患者組織中表達(dá)降低提示其預(yù)后較差。Chiu等[28]指出1型糖原貯積病導(dǎo)致的肝細(xì)胞腺瘤患者與1型糖原貯積病無肝細(xì)胞腺瘤患者和其他原因?qū)е碌母渭?xì)胞腺瘤患者比較，前者肝細(xì)胞中miR-424表達(dá)下降，而原發(fā)性肝癌細(xì)胞系中miR-424表達(dá)顯著下降。Yang等[29]發(fā)現(xiàn)miR-424在肝癌組織及細(xì)胞系中表達(dá)降低，并且miR-424的表達(dá)量與肝癌患者預(yù)后呈正相關(guān)。

基礎(chǔ)研究表明，miR-424高表達(dá)可以抑制肝癌細(xì)胞增殖、遷移、浸潤。MiR-424可使肝癌細(xì)胞SK-TRb阻滯細(xì)胞周期在G1期；體內(nèi)及體外研究發(fā)現(xiàn)甲狀腺激素可通過誘導(dǎo)miR-424/503前體轉(zhuǎn)錄，從而抑制表達(dá)核受體b(TRb)的肝癌細(xì)胞增殖、遷移及浸潤[30]。Zhang等[31]發(fā)現(xiàn)失巢凋亡抵抗的肝癌細(xì)胞miR-424-5p表達(dá)顯著降低，在肝癌細(xì)胞中過表達(dá)miR-424-5p直接靶向抑制β-連環(huán)蛋白/T細(xì)胞因子抑制子，維持細(xì)胞膜上E-cadherin/β-catenin復(fù)合物，可逆轉(zhuǎn)失巢凋亡抵抗、阻止上皮間質(zhì)轉(zhuǎn)化、抑制遷移活性；裸鼠研究證實了上述結(jié)果；人體研究發(fā)現(xiàn)肝癌組織與正常肝組織比較miR-424-5p顯著下調(diào)，miR-424-5p的表達(dá)與重度病理分級和TNM分級呈負(fù)相關(guān)，且血清中miR-424-5p表達(dá)趨勢與組織中一致。Yu等[32]進(jìn)一步明確miR-424表達(dá)在肝癌原位組織及細(xì)胞系中均下調(diào)，而過表達(dá)miR-424可靶向致癌基因c-Myb，抑制癌細(xì)胞增殖、轉(zhuǎn)移和浸潤。Yang等[29]發(fā)現(xiàn)miR-424可抑制Akt3/E2F3軸以抑制肝癌生長。Han等[33]指出肝癌腫瘤起始細(xì)胞中miR-424表達(dá)降低，miR-424等4個miRNAs可協(xié)同靶向維持TICs的關(guān)鍵因子B淋巴細(xì)胞白血病前體蛋白轉(zhuǎn)錄因子3和電壓門控鈣離子通道α2δ1。

5 胰腺癌

研究顯示，miR-424在胰腺癌患者組織中表達(dá)升高，促進(jìn)胰腺癌發(fā)展[34]。Wu等[35]發(fā)現(xiàn)miR-424-5p直接靶向細(xì)胞因子信號傳導(dǎo)抑制蛋白6，活化ERK1/2信號通路，促進(jìn)胰腺癌細(xì)胞增殖、遷移和浸潤并抑制細(xì)胞凋亡，促進(jìn)腫瘤發(fā)展。該發(fā)現(xiàn)有利于胰腺癌更好的診斷、預(yù)測預(yù)后及選擇治療方式。

6 結(jié)直腸癌

研究顯示，miR-424在結(jié)直腸癌患者中的表達(dá)與在結(jié)直腸癌細(xì)胞系中的表達(dá)不同。Wang等[36]發(fā)現(xiàn)在無淋巴結(jié)轉(zhuǎn)移的結(jié)腸癌患者中，癌變組織中的miR-424表達(dá)比癌旁組織明顯上調(diào)。Guo等[37]證實在結(jié)直腸癌中miR-424表達(dá)上調(diào)。中國結(jié)直腸癌患者的miR-424表達(dá)比正常結(jié)直腸顯著增高，但未發(fā)現(xiàn)miR-424與生存曲線存在相關(guān)性；體外研究發(fā)現(xiàn)結(jié)直腸癌細(xì)胞系HCT116和HT-29中的miR-424與正常結(jié)直腸黏膜比較表達(dá)下降[38]。Gaur等[39]發(fā)現(xiàn)miR-424在7種人結(jié)直腸癌細(xì)胞系中表達(dá)下降。出現(xiàn)這種體內(nèi)體外相反結(jié)果，可能由于HCT116和HT-29細(xì)胞系來源于高加索人，即miR-424的表達(dá)可能與人種有關(guān)。Wang等[40]發(fā)現(xiàn)在手術(shù)冰凍組織和結(jié)腸鏡活檢組織中，在結(jié)腸癌中miR-424與miR-375表達(dá)均顯著下調(diào)，而miR-92a表達(dá)顯著上調(diào)，用miR-424結(jié)合miR-375、miR-92a制作評定模型(Logit模型)，用于區(qū)分結(jié)腸癌和腺瘤的準(zhǔn)確率為94%，用于區(qū)分結(jié)腸癌與高分化上皮內(nèi)腫瘤的準(zhǔn)確率為89%。此外，通過對Ⅰ-Ⅳ期結(jié)腸癌患者miRs測定發(fā)現(xiàn)miR-424與腫瘤轉(zhuǎn)移程度呈負(fù)相關(guān)[41]。

Guo等[37]指出miR-424對結(jié)直腸癌的作用不是通過靶向胰島素樣生長因子1受體。Wang[40]證實miR-424與其可能靶物—MAP2K1，MAPK3，SMAD3，WNT1，WNT7A 和MAP2K4的mRNA呈顯著負(fù)相關(guān)。體外過表達(dá)miR-424時腫瘤細(xì)胞侵襲性降低[41]。在人直腸癌細(xì)胞系HCT116中miR-424可靶向Cdc25A，抑制細(xì)胞周期蛋白依賴性激酶2磷酸化，促進(jìn)細(xì)胞周期G1期阻滯[42]。在人結(jié)腸癌、前列腺癌等腫瘤細(xì)胞中miR-424/503簇受抑制后介導(dǎo)Rictor上調(diào)，導(dǎo)致mTORC2復(fù)合物形成并使其活化，活化的mTORC2可活化AKT，以促進(jìn)細(xì)胞增殖、轉(zhuǎn)移和腫瘤生長及進(jìn)展[43]。以上研究提示miR-424具有抑制結(jié)直腸癌的作用。

7 骨肉瘤

研究顯示，miR-424表達(dá)在成骨肉瘤中上調(diào)，具有抑制骨肉瘤增殖、遷移、浸潤的作用。Palmieri等[44]發(fā)現(xiàn)在多孔聚乙烯作用下人成骨肉瘤細(xì)胞系MG-63中miR-424表達(dá)上調(diào)。在人骨肉瘤細(xì)胞系U2OS中miR-424可靶向Cdc25A，抑制細(xì)胞周期蛋白依賴性激酶2(cdk2)磷酸化，促進(jìn)細(xì)胞周期G1期阻滯[42]。Long等[45]證明miR-424作為腫瘤抑制物可靶向脂肪酸合成酶，下調(diào)其mRNA及蛋白水平，從而抑制骨肉瘤細(xì)胞系U2OS的遷移和浸潤。

8 皮膚和頭頸部鱗狀細(xì)胞癌

研究顯示，miR-424的表達(dá)在皮膚、舌、咽喉鱗狀細(xì)胞癌中表達(dá)均上調(diào)[46,47]。Sand等[9]通過miRs微陣列分析發(fā)現(xiàn)皮膚鱗狀細(xì)胞癌患者病灶處與病灶周邊正常組織對比miR-424表達(dá)顯著增加。Boldrup等[46]發(fā)現(xiàn)miR-424在舌鱗狀細(xì)胞癌細(xì)胞中表達(dá)上調(diào)，而miR-424表達(dá)在病灶周圍正常的舌組織中與完全正常舌組織比較表達(dá)下降，提示miR-424可能作為癌變范圍的生物標(biāo)記物，并對舌鱗狀細(xì)胞癌的生長有作用。然而，Yata等[47]發(fā)現(xiàn)miR-424表達(dá)在頭頸部鱗狀細(xì)胞癌腫瘤干細(xì)胞表達(dá)低于普通腫瘤細(xì)胞。

9 其他腫瘤

在腎癌細(xì)胞系786-O中miR-424表達(dá)下調(diào)，靶向G2/M期檢查點(diǎn)的關(guān)鍵激酶WEE1，進(jìn)而使有絲分裂細(xì)胞周期依賴性蛋白激酶Cdc2活化，抑制增殖、取消G/M期阻滯以進(jìn)入有絲分裂、促進(jìn)凋亡[48]。在膀胱癌組織中miR-424表達(dá)降低，與膀胱癌惡性生長、高臨床分級及不良預(yù)后相關(guān)，上調(diào)miR-424可通過靶向EGFR而抑制AKT信號通路從而抑制膀胱癌生長率及侵襲性[49]。并且DNA甲基轉(zhuǎn)移酶DMNT1可抑制miR-424的轉(zhuǎn)錄[49]。在人前列腺癌細(xì)胞系DU145新建轉(zhuǎn)移模型DU145-LN4中間質(zhì)向上皮細(xì)胞轉(zhuǎn)換機(jī)制之一為下調(diào)miR-424；過表達(dá)miR-424可出現(xiàn)上皮向間質(zhì)細(xì)胞轉(zhuǎn)化[50]。甲狀腺乳頭狀癌中miR-424表達(dá)明顯上調(diào)，并與腫瘤侵襲性相關(guān)[51]。

Zhang等[52]通過體內(nèi)外試驗對腫瘤相關(guān)成纖維細(xì)胞CAFs研究發(fā)現(xiàn)：CAF形成時miR-424表達(dá)升高，直接靶向氧化磷酸化向糖酵解轉(zhuǎn)化的代謝開關(guān)—異檸檬酸脫氫酶3復(fù)合物的α亞基，減低α-酮戊二酸與琥珀酸和延胡索酸的比率，從而抑制脯氨酸羥化酶活性，使HIF-1α保持穩(wěn)定，促進(jìn)CAF的糖酵解抑制氧化磷酸化，促進(jìn)腫瘤生長。

10 miR-424與抗腫瘤藥物

除了對腫瘤細(xì)胞的作用外，miR-424還影響腫瘤對化療藥物的敏感性。Vilquin等[53]發(fā)現(xiàn)miR-424表達(dá)在穩(wěn)定轉(zhuǎn)染人芳香化酶基因的MCF-7aro(ER+乳腺癌細(xì)胞株) 中高于芳香酶抑制劑抵抗的細(xì)胞系包括Res-Let(來曲唑抵抗)、Res-Ana(阿那曲唑抵抗)；而在芳香酶抑制劑藥物敏感的MCF-7aro細(xì)胞中抑制miR-424表達(dá)可顯著降低細(xì)胞對來曲唑的敏感性；該作用可能與miR-424抑制PI3K/AKT/mTOR通路活化有關(guān)。癌干細(xì)胞中miR-424的高表達(dá)與卵巢癌化療抵抗和腫瘤進(jìn)展相關(guān)[54]。但是，Cecco等[55]指出，使用含未甲基化胞嘧啶-磷酸二酯鍵-鳥嘌呤基序的寡脫氧核糖核苷酸治療人卵巢癌細(xì)胞系IGROV-1種植小鼠，與鹽水治療相比miR-424表達(dá)顯著下降，但miR-424表達(dá)的下降對順鉑毒性未見顯著促進(jìn)作用。在腫瘤細(xì)胞(黑色素瘤細(xì)胞A375、膠質(zhì)母細(xì)胞瘤細(xì)胞U251、結(jié)腸癌細(xì)胞HCT116)中低氧誘導(dǎo)pri-miR-424和成熟miR-424高表達(dá)，而過表達(dá)miR-424可降低腫瘤細(xì)胞對化療藥物阿霉素和依托泊甙的敏感性，抑制miR-424則出現(xiàn)相反作用；其機(jī)制為HIF1α與pri-miR-424啟動子區(qū)上游的低氧反應(yīng)域(HRE)結(jié)合，促進(jìn)miR-424轉(zhuǎn)錄，并miR-424靶向PDCD4(腫瘤抑制物)，進(jìn)而抑制凋亡、降低腫瘤對化療的敏感性；裸鼠腫瘤異種種植模型也證實過表達(dá)miR-424可增加腫瘤對阿霉素的抵抗性；臨床分析發(fā)現(xiàn)乳腺癌組織中miR-424與PDCD4呈負(fù)相關(guān)[56]。與此相反，Pouliot等[57]發(fā)現(xiàn)降低miR-424表達(dá)可介導(dǎo)腫瘤細(xì)胞出現(xiàn)順鉑抵抗，而過表達(dá)miR-424可通過靶向細(xì)胞周期激酶WEE1和CHK1促進(jìn)順鉑抵抗的惡性腫瘤細(xì)胞凋亡?？梢妋iR-424對不同的抗腫瘤藥物作用機(jī)理不同，因而產(chǎn)生不同應(yīng)答。

11 小結(jié)

總之，目前miR-424在腫瘤中的研究多集中在對miR-424表達(dá)變化方面，進(jìn)一步的機(jī)制研究較少，缺乏全面的機(jī)制研究。MiR-424在不同腫瘤中表達(dá)可能相反，也有研究發(fā)現(xiàn)miR-424在同一種腫瘤發(fā)展的不同時期表達(dá)不同并且作用不同，在腫瘤早期可能促進(jìn)腫瘤生長，而在腫瘤后期則表現(xiàn)為抑制作用[17]。以上研究指出miR-424的表達(dá)受多種因素的影響，其可作為腫瘤診斷、分期、預(yù)后的生物標(biāo)記物，可用于明確腫瘤范圍，也可作為腫瘤的治療靶物，因此有必要進(jìn)行更進(jìn)一步的機(jī)制研究，以期應(yīng)用于臨床。

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Progress in research on the role of microRNA-424 in carcinogenesis and its related mechanism

LIU Ping1, ZHAO Hai-ping2, LUO Yu-min1，2*

(1.Department of Neurology, 2. Department of Cerebrovascular Diseases, Xuanwu Hospital,Capital Medical University, Beijing 100053, China)

A member of miR-16 family, miR-424 has been found to be closely related with tumorigenesis, tumor progrssion, prognosis and therapy. This article reviews the expression changes, roles and possible regulating mechanisms of miR-424 in leukemia and various tumors such as breast, cervical, lung, liver and colorectal cancers. Recent studies have demonstrated that the expression of miR-424 is affected by many factors, and miR-424 could be a biomarker of diagnosis, staging and prognosis in cancers,to identify the area of tumor, and be a target of therapy.

miR-424; Neoplasms; Leukemia

國家自然科學(xué)基金項目(81571280, 81201028,30770743)。

劉萍(1983-)，女，醫(yī)師，博士，研究方向：腦血管病轉(zhuǎn)化醫(yī)學(xué)研究。E-mail: heliu1056@163.com

羅玉敏，教授，研究方向：腦血管病發(fā)病機(jī)制。E-mail: yumin111@ccmu.edu.cn

研究進(jìn)展

Q95-33

A

1005-4847(2016)05-0529-06

10.3969.j.issn.1005-4847. 2016.05.017

2016-03-09